1-phenyl-3-methoxy; hydroxy; or benzyloxy-5-sulfanilamido pyrazole-1, 2 and derivatives thereof



2,988,547 -SULFANIL EREOF AMIDO June 13, 1961 J. D. AcHELls ET AL l-PHENYL--METHOXY; HYDROXY; OR BENZYLOXY-5 Mmmm-1,2 AND DERIVATIVES TH Filed March 25, 1960 Unite States Parent' 2,988,547 LPHENYL-S-METHQXY; HYDROXY; OR BENZYL- OXY 5 SULFANILAMIDO PYRAZOLE1,2 AND DERIVATIVES THEREOF Johann Daniel Achelis and Erich Haack, Heidelberg, 'and Rudi Gall, Ruth Heerdt, and Wolfgang Voemel, Mannheim, Germany, assignors to C. F. Boehringer & Soehne, Mannheim-Waldhof, Germany, a company of Germany Filed Mar. 25, 1960, Ser. No. 17,593 Claims priority, application Germany Mar. 28, 1959 Claims. (Cl. 260--239.9)

The present invention relates to a valuable pyrazole compound and more particularly to l-phenyl-S-methoxy- 5-sulfanilamido py-razole and to a process Iof making same.

There have been known only a few sulfoamides of the pyrazole series. S-sulfanilamido pyrazole1,2 has been reported to have a good eifect against pneumococci. S-Sulfanilamido-S-methyl pyrazole-1,2 and 5-sulfanilamido-3-methyl-lphenyl-pyrazolel,2 have also been described. Recently 5-sulfanilamido-l-phenyl pyrazolel,2, i.e. a phenyl pyrazole compound which is unsubstituted in 3-position has been marketed. These known sulfanilamido pyrazole compounds, however, have a number of disadvantages. For instance, S-sulfanilamido-3-rnethyl pyraZole-1,2 produces a rather low sulfonamide blood level, i.e., its absorption by the mucous membranes of the intestines is unsatisfactory so that it cannot be employed in the treatment of diseases which are ordinarily and successfully treated with sulfonamides such as pneumonia, angina, cystopyelitisr, cholecystitis, and the like. l-phenyl-S-sulfanilamido pyrazole-1,2 and l-phenyl-3- methyl-S-sulfanilamido pyrazole-1,2 have a rather unsatisfactory efect upon Streptococcus infections as has been proved by tests with mice infected intraperitoneally with a high-ly pathogenic Streptococcus pyogenes Aronson species. l

It is one object of the present invention to provide a new and valuable sulfonamide of the pyrazole series which is substituted by a phenyl radical in l-position and by a methoxy group in 3position.

Another object of the present invention is to provide a new and valuable pharmaceutical which has a high chemotherapeutic activity against both gram-positive and gram-negative bacteria, which is highly soluble so that it is readily absorbed into the blood stream, and which provides a long-lasting high blood level.

A further object of the present invention is to provide a simple and effective p-rocess of making such a compound.

These and other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

It has been found that 1-phenyl-3-methoxy-S-sulfanilamido pyrazole of the formula `compound will crystallize inthe kidneys or inthe urinary tract. This favorable combination of physico-chemical, bacteriostatic, and pharmacological properties renders the new compound especially valuable and provides a new compound which is significantly superior -to sulfonamides of the pyrazole series known heretofore.

The sulfanilamido pyrazole according to the present invention can be obtained according to known processes. For instance, sulfonyl halides of the formula wherein W is an amino group or a group convertible into an amino group, s-uch as an acylamino or a nitro group are reacted with 1-phenyl-B-methoxy-S-amino pyrazole- 1,2. The substituent W, if necessary, is converted into the amino group.

In place of 1phenyl3methoxy5amino pyrazole-l,2, amino pyrazoles of the formula wherein X is a hydroxyl group or a group which can be converted into the hydroxyl group, for instance, a tosylate group or another sulfonate group, r

can be used as the one reaction component for condensation with the sulfonyl halide and the substituent X in the resulting condensation product is then subsequently converted into the methoxy group according to known m'ethods.

The reciprocal method, i.e. the reaction of the corresponding halogopyrazole compounds with sulfonyl amides or their alkali metal salts can also be employed.

The following examples serve tol illustrate the present invention without, however, limiting the same thereto.

EXAMPLE l 45.1 g. of l-phenyl-3-methoxy-5-amino pyrazole-LZ hydrochloride (melting point: C.) which has been prepared by methylating the corresponding 3hydroxy pyrazole compound by means of an ethereal diazomethane solution with the addition of methanol, and subsequent precipitation with hydrogen chloride (see l. Am. Chem. Soc., vol. 65 (1943), p. 52) andv 98.1 g. of acetyl sulfanilyl chloride are suspended in 200 cc. of absolute methylene chloride. An about 20% solution of t-rimethylamine in `dry benzene is added drop by drop toV this mixture while heating runder reux and stirring, until the resulting solution is rendered exactlyY neutral. This solution is reuxed for 6 hours during which time the pH-value is controlled continuously and additional trimethylamine solution is added if required. After the addition of 200 cc. of water, the organic solvents are distilled off in a vacuum. The aqueous solution 1s allowed to'cool and the precipitated crystals are filtered off by suction. 99.8 g. (yield: 86%) of 1-phenyl-S-methoXy-S-(bis-acetyl su1fanilyl) amino pyrazole-LZ are obtained. Melting point, yafter recrystallization from ethanol: 239-24l C.

Said bis-sulfonyl compound is reuxed with 7.75 moles of sodium hydroxide in the form of a 10% aqueous solution until `a clear solution has been formed. Heating for 3 about 90 minutes is required. The reaction mixture is then heated for another hour, purified with animal charcoal, filtered, and acidied with dilute hydrochloric acid.

.In this manner 53.3 g. (yield: 90%) of 1-phenyl-3-methof the components in absolute ethylene chloride.

EXAMPLE 2 7 g. of 1-phenyl-3-benzyloxy-S-amino pyrazole-l,2 prepared by reacting the potassium salt of l-phenyl-B-hydroxy-S-amino pyrazole-L2 with benzylchloride in dimethyl formamide at 50 C. and having the melting point of 82-83.5 C. after recrystallization from ethanol, and 13.5 g. of acetyl sulfanilyl chloride are suspended in 150 cc. of anhydrous ethylene chloride. Gaseous trimethylamine is introduced into the mixture to a pH-value of 8.0. Stirring is continued for one hour while keeping the pH at 8.0 by the addition of trimethylamine, if necessary. Water is added to the resulting clear solution and the precipitated crystals are filtered olf. g. (i.e. a yield of 86%) of 1phenyl3-benzyloxy-S-(bis-acetyl sulfanilyl) amino pyrazole-l,2 of the melting point 102 `C. (with decomposition) are obtained.

The benzyl group is split oft by dissolving said compound in a mixture of methanol and dioxane (2:1) and introducing hydrogen into the solution in the presence of a palladium catalyst. On concentrating the solution by evaporation in a vacuum, l-phenyl-3-hydroxy-S-(bisacetyl sulfanilyl) `amino pyrazole-l,2 crystallizes; melting point: 227 C. (with decomposition).

The crude compound is suspended in a mixture of methanol Iand dimethyl acetamide (4:1). -An ethereal diazomethane solution is added Ithereto until the color of the mixture remains yellow. Thereby rapid dissolution and vigorous evolution of nitrogen takes place. Excess diazomethane is destroyed by the addition of glacial acetic acid. The resulting solution -is concentrated by evapora-tion in a vacuum and the concentrate is diluted with water, thereby causing crystallization. The resulting 1-phenyl-B-methoxy-S-(bis-acetyl sulfanilyl) lamino pyrazole1,2 is saponied in the same manner as described in Example 1. The resulting product of hydrolysis is recrystallized from ethanol. It proved to be identical with 1-phenyl-3-methoxy-S-sulfanilamido pyrazole-1,2 obtained according to Example 1.

The following tests demonstrate the superiority of the new l-phenyl-S-methoxy-S-sulfanilamido pyrazolel,2, hereinafter designated as compound A, over the known l-phenyl-S-sulfanilamido pyrazole-l,2 which is unsubstituted in 3-position and which is designated hereinafter as compound B. They also prove the clinical utility of the new compound.

TEST A Solubility in water 'bility is higher than that of compound B. Thus, even under extremely unfavorable conditions, such as very small amounts of urine, crystallization in the urinary pas- 4 sages is excluded. The solubilities in water at 37 C. are given in Table I in mg./cc.:

TAB LE I Compound pH 6.5 pH 7.6

l-phenyl-3-methoxy-5-sulfanilamldo pyrazole 22 320 l-phenyl-3-methoxy-5-acetyl sulfanilamido pyrazole 65 1, 202 1phenyl5su1fanilamido pyrazole 19 305 l-phenyl--acetyl sulfanilamido pyrazoie 45 665 TEST B The acute toxicity of 1-pheny1-3-methoxy-S-sulfanilamide pyrazole-1,2, determined by intravenous administration to mice, is only about of that of compound B as shown in the following Table II which gives the dose causing death of 50% of the animals (LD50):

TABLE II Compound LD50, gJkg.

Compound A 1.0 Compound B 0.42

Tnsr C Bacleriostatc effect n vitro The bacteriostatic effect of compounds A and B was determined on a large number of pathogenic microorganisms. The following Table III illustrates this effect on a few of said microorganisms, namely on bacteria which are responsible for diseases that are preferably treated with sulfonamides. These tests in vitro serve merely as a base for .the therapeutic-al tests with animals which will be described hereinafter and which are even more adapted for an evaluation of the sulfonamides than said in vitro tests.

It is evident that the new l-phenyl-3-methoxy-S-sulfanlamido pyrazole-l,2 is at least as effective as the known l-phenyl-S-sulfanilamido pyrazole-1,2 which is unsubstituted in 3-position.

TBsr D Therapeutic tests with mice Therapeutic tests with mice are considered as the most important base for evaluating the therapeutical effect of sulfonamides.

In the following tests while inbred mice were infected intraperitoneally with many times the lethal amount of the microorganism. The infected mice received, thereafter, perorally specific daily doses of the two compounds A or B in the form of their free bases. The therapeutic effectiveness of the sulfonamides was evaluated by the number of animals surviving for tive days after treatment was suspended. All infected control animals which were not treated, died lwithin 5 days after the infection.

TABLE IV Surviving mice in percent of total No.

daily dose, Com- On the Microorganism mg./ pound On the tenth day kg. fifth day of test (5 (end of days after treatment) termination of treatment) ,S'tgnlococcua pz/oaenes (Strain 20 Di Lococcus pneumoniae A 90 40 ("iype II 320 iB 20 o Salmonella typhzmurzum 320 g Listeria monocytogenes Strain 80 {A 95 95 1145). B 39 l0 Clinical tests with humans to determine the sulfonamide serum level At present it is justied to introduce new sulfonamides is therapy provided they produce long-lasting blood levels, so that relatively small doses given in large intervals are suicient to successfully treat infectious diseases.

In these tests 1-phenyl-3-methoxy-S-sulfanilamidopyrazole1,2 and l-phenyl-S-sulfanilamido pyrazole-1,2 were administered to volunteers in a single oral dose of l5 mg./kg. of body Weight (about 1 g. of an adult person of average weight). The serum levels of total sulfonamide yand free sulfonamide were determined at various 35 2858309 intervals according to the method of Bratton and Marsha1. Both sulfonamides were administered to the same 4 test persons in exactly the same manner. The values observed thereby are plotted in the attached curves. The

curves illustrated in FIG. 1 show the mean serum level on administration of 1-phenyl-3-methoXy-S-sulfanilamido pyrazole1,2 while the curves illustrated in FIG. 2 show the mean serum level on administration of 1phenyl5 sulfanilamido pyrazole1,2. It is evident that the serum levels with compound A are substantially higher than do not decrease as rapidly as those with compound B. The ratio of the total sulfonamide serum level of compound B to compound A is as follows:

4 hours after administration 1:1.3 8 hours after administration 1:1.6 12 hours after administration 1:2.2 24 hours after administration 1:3.5 48 hours after administration 1:8.0

The half-life period, i.e. the period of time within which a speciiic serum level decreases to half its initial value was on the average 43 hours for 1-phenyl-3-methoxy-S-sulfanilamido pyrazole-1,2 and only 13 hours for 1-phenyl-5-sulfanilamdo pyrazole-1,2.

We claim:

2. 1phenyl 3 methoxy-S-(bis-acetyl sulfanilyl) amino pyrazo1e-1,2.

3. l-phenyl-S-methoxy-S-acetyl sulfanilamido pyrazole- 1,2.

4. 1phenyl 3 hydroxy-S-(bis-acetyl sulfanilyl) amino pyrazole-LZ.

References Cited in the le of this patent UNITED STATES PATENTS Druey et al Oct. 28, 1958 FOREIGN PATENTS 1,049,384 Germany Jan. 29, 1959 876,296 France July 27, 1942 

5. 1-PHENYL-3-BENZYLOXY-5-(BIS-ACETYL SULFANILYL) AMINO PYRAZOLE-1,2. 